Tag: intramyocardial stem cell injections

In April of 2013, the results of three clinical trials that examined the effects of bone marrow-derived stem cell treatments in patients with acute myocardial infarction (translation – a recent heart attack) or chronic heart failure. These trials were the SWISS-AMI trial, the CELLWAVE trial, and the C-CURE trial.

The SWISS-AMI trial (Circulation. 2013;127:1968-1979), which stands for the Swiss Multicenter Intracoronary Stem Cells Study in Acute Myocardial Infarction trial, was designed to examine the optimal time of stem cell administration at 2 different time points: early or 5 to 7 days versus late or 3 to 4 weeks after a heart attack. This trial is an extension of the large REPAIR-AMI, which showed that patients who tended to receive bone marrow stem cell treatments later rather than earlier had more pronounced therapeutic effects from the stem cell treatments.

SWISS-AMI examined 60 patients who received standard cardiological care after a heart attack, 58 who received bone marrow stem cells 5-7 days after a heart attack, and 49 patients who received bone marrow stem cells 3-4 weeks after their heart attacks. All stem cells were delivered through the coronary arteries by means of the same technology used to deliver a stent.

When the heart function of all three groups were analyzed, no significant differences between the three groups were observed. Those who received stem cell 5-7 days after a heart attack showed a 1.8% increase in their ejection fractions (the percentage of blood that is ejected from the ventricle with each beat) versus an average decrease of 0.4% in those who received standard care, and a 0.8% increase in those who received their stem cells 3-4 weeks after a heart attack. If these results sound underwhelming it is because they are. The standard deviations of each group so massive that these three groups essentially overlap each other. The differences are not significant from a statistical perspective. Thus the results of this study were definitely negative.

The second study, CELLWAVE (JAMA, April 17, 2013—Vol 309, No. 15, 1622-1631), was a double-blinded, placebo-controlled study conducted among heart attack patients between 2005 and 2011 at Goethe University Frankfurt, Germany. In this study, the damaged area of heart was pretreated with low-energy ultrasound shock waves, after which patients in each group were treated with either low dose stem cells, high-dose stem cells, or placebo. Patients also received either shock wave treatment or placebo shock wave treatment. Thus this was a very well-controlled study. Stem cells were administered through the coronary arteries, just as in the case of the SWISS-AMI study.

The results were clearly positive in this study. The stem cell + shock wave treatment groups showed definite increases in heart function above the placebo groups, and showed fewer adverse effects. The shock wave treatments seem to prime the heart tissue to receive the stem cells. The shock waves induce the release of cardiac stromal-derived factor-1, which is a potent chemoattractor of stem cells. This is an intriguing procedure that deserves more study.

The third study, C-CURE, is definitely the most interesting of the three (Bartunek et al. JACC Vol. 61, No. 23, June 11, 2013:2329–38). In this trial, mesenchymal stromal cells (MSCs) were isolated from bone marrow and primed with a cocktail of chemicals that pushed the stem cells towards a heart muscle fate. Then the cells were transplanted into the heart by direct injection into the heart muscle as guided by NOGA three-dimensional imaging of the heart.

After initially screening 320 patients with chronic heart failure, 15 were treated with standard care and the other 32 received the stem cell treatment. After a two-year follow-up, the results were remarkable: those who received the stem cell treatment showed an average 7% increase in ejection fraction versus 0.2% for receiving standard care, an almost 25 milliliter reduction in end systolic volume (measures degree of dilation of ventricle – not a good thing and the fact that it decreased is a very good thing) versus a 9 milliliter decrease for those receiving standard care, and were able to walk 62 meters further in 6 minutes as opposed to standard care group who walked 18 meters less in 6 minutes.

While these studies do not provide definitive answers to the bone marrow/heart treatment debate, they do extend the debate. Clearly bone marrow stem cells help some patients and do not help others. The difference between these two groups of patients continues to elude researchers. Also, how the bone marrow is processed is definitely important. When the cells are administered also seems to be important, but the exact time slot is not clear in human patients. It is also possible that some patients have poor quality bone marrow in the first place, and might be better served by allogeneic (someone else’s stem cells) treatments rather than autologous (the patient’s own stem cells) stem cell treatments.

Also, stem cell treatments for heart patients will probably need to be more sophisticated if they are to provide greater levels of healing. Heart muscle cells are required, but so are blood vessels to feed the new heart muscle. If mesenchymal stem cells work by activating resident heart stem cells, then maybe mesenchymal transplants should be accompanied by endothelial progenitor cell transplants (CD117+, CD45+ CD31+ cells from bone marrow) to provide the blood vessels necessary to replace the clogged blood vessels and the new heart muscle that is grown.

A consortium of Portuguese scientists have conducted an extensive examination of the effects of mesenchymal stromal cells from umbilical cord on the heart of mice that have suffered a massive heart attack. Even more remarkable is that these workers used a proprietary technique to harvest, process, and prepare the umbilical cord stem cells in the hopes that this technique would give rise to a commercial product that will be tested in human clinical trials,

Human umbilical cord tissue-derived Mesenchymal Stromal Cells (MSCs) were obtained by means of a proprietary technology that was developed by a biomedical company called ECBio. Their product,, UCX®, consists of clean, high-quality, umbilical cord stem cells that are collected under Good Manufacturing Practices. The use of Good Manufacturing Practice means that UCX is potentially a clinical-grade product. Thus, this paper represents a preclinical evaluation of UCX.

This experiments in this paper used standard methods to give mice heart attacks that were later received injections of UCX into their heart muscle. The same UCX cells were used in experiments with cultured cells to determine their effects under more controlled conditions.

The mice that received the UCX injections into their heart muscles after suffering from a large heart attack showed preservation of heart function. Also, measurements of the numbers of dead cells in the heart muscle of heart-sick mice that did and did not receive injections of umbilical cord cells into their hearts showed that the umbilical cord stem cells preserved heart muscle cells and prevented them from dying. Additionally, the implanted umbilical cord MSCs induced the growth and formation of many small blood vessels in the infarcted area of the heart. This prevented the heart from undergoing remodeling (enlargement), and preserved heart structure and function.

When subjected to a battery of tests on cultured cells, UCX activated cardiac stem cells, which are the resident stem cell population in the heart. Implanted UCX cells activated the proliferation of cardiac stem cells and their differentiation into heart muscle cells. There was no evidence that umbilical cord MSCs differentiated into heart muscle cells and engrafted into the heart. Rather UCX seems to help the heart by means of paracrine mechanisms, which simply means that they secrete healing molecules in the heart and help the heart heal itself.

In conclusion, Diana Santos Nascimento, the lead author of this work, and her colleagues state that, “the method of UCX® extraction and subsequent processing has been recently adapted to advanced therapy medicinal product (ATMP) standards, as defined by the guideline on the minimum quality data for certification of ATMP. Given that our work constitutes a proof-of-principle for the cardioprotective effects UCX® exert in the context of MI, a future clinical usage of this off-the-shelf cellular product can be envisaged.”

Preclinical trials with larger animals should come next, and after that, hopefully, the first human clinical trials will begin.

Researchers from the famed Mayo Clinic, in collaboration with scientists at a biopharmaceutical biotechnology company in Belgium have invented a specialized catheter for transplanting stem cells into a beating heart.

This new device contains a curved needle with graded openings along the shaft of the needle. The cells are released into the needle and out through the openings in the side of the needle shaft. This results in maximum retention of implanted stem cells to repair the heart.

“Although biotherapies are increasingly more sophisticated, the tools for delivering regenerative therapies demonstrate a limited capacity in achieving high cell retention in the heart,” said Atta Behfar, the lead author of this study and a cardiologist. “Retention of cells is, of course, crucial to an effective, practical therapy.”

Researchers from the Mayo Clinic Center for Regenerative Medicine in Rochester, MN and Cardio3 Biosciences in Mont-Saint-Guibert, Belgium, collaborated to develop the device. Development of this technology began by modeling the dynamic motions of the heart in a computer model. Once the Belgium group had refined this computer model, the model was tested in North America for safety and retention efficiency.

These experiments showed that the new, curved design of the catheter eliminates backflow and minimizes cell loss. The graded holes that go from small to large diameters decrease the pressures in the heart and this helps properly target the cells. This new design works well in healthy and damaged hearts.

Clinical trials are already testing this new catheter. In Europe, the CHART-1 clinical trial is presently underway, and this is the first phase 3 trial to examine the regeneration of heart muscle in heart attack patients.

These particular studies are the culmination of years of basic science research at Mayo Clinic and earlier clinical studies with Cardio3 BioSciences and Cardiovascular Centre in Aalst, Belgium, which were conducted between 2009 and 2010. This study, the C-CURE or Cardiopoietic stem Cell therapy in heart failURE study examined 47 patients, (15 control and 32 experimental) who received injections of bone marrow-derived mesenchymal stem cells from their own bone marrow into their heart muscle. Control patients only received standard care. After six months, those patients who received the stem cell treatment showed an increase in heart function and the distance they could walk in six minutes. No adverse effects were observed in the stem cell recipients.

This study established the efficacy of mesenchymal stem cell treatments in heart attack patients. However, other animal and computer studies established the efficacy of this new catheter for injecting heart muscle with stem cells. Hopefully, the results of the CHART-1 study will be available soon.

Postscript: The CHART-2 clinical trial is also starting. See this video about it.

Angina pectoris is defined as chest pain or discomfort that results from poor blood flow through the blood vessels in the heart and is usually activated by activity or stress.

In Los Angeles, California, physicians have initiated a double-blind, multicenter Phase III clinical trial that uses a patient’s own blood-derived stem cells to restore circulation to the heart of angina patients.

This procedure utilizes state-of-the-art imaging technology to map the heart and generate a three-dimensional image of the heart. These sophisticated images will guide the physicians as they inject stem cells into targeted sites in the heart.

This is a double-blinded study, which means that neither the patients nor the researcher will know who is receiving stem-cell injections and who is receiving the placebo.

The institution at which this study is being conducted, University of Los Angeles (UCLA), is attempting to establish evidence for a stem cell treatment that might be approved by the US Food and Drug Administration for patients with refractory angina. The subjects in this study had received the standard types of care but did not receive relief. Therefore by enrolling in this trial, these patients had nothing to lose.

Dr. Ali Nasir, assistant professor of cardiology at the David Geffen School of Medicine and co-principal investigator of this study, said: “We’re hoping to offer patients who have no other options a treatment that will alleviate their severe chest pain and improve their quality of life.”

Before injecting the stem cells or the placebo, the team examined the three-dimensional image of the heart and ascertained the health of the heart muscle and voltage it generated. Damaged areas of the heart fail to produce adequate quantities of voltage and show low levels of energy.

Jonathan Tobis, clinical professor of cardiology and director of interventional cardiology research at Geffen School of Medicine, said: “We are able to tell by the voltage levels and motion which area of the [heart] muscle is scarred or abnormal and not getting enough blood and oxygen. We then targeted the injections to the areas just adjacent to the scarred and abnormal heart muscle to try to restore some of the blood flow.”

What did they inject? The UCLA team extracted bone marrow from the pelvic bones and isolated CD34+ cells. CD34 refers to a cell surface protein that is found on bone marrow stem cells and mediates the adhesion of bone marrow stem cells to the bone marrow matrix. It is found on the surfaces of hematopoietic stem cells, placental cells, a subset of mesenchymal stem cells, endothelial progenitor cells, and endothelial cells of blood vessels. These are not the only cells that express this cell surface protein, but it does list the important cells for our purposes. Once the CD34+ cells were isolated, the were injected into the heart through a catheter that was inserted into a vein in the groin.

The team hopes that these cells (a mixture of mesenchymal stem cells, hematopoietic stem cells, and endothelial progenitor cells) will stimulate the growth of new blood vessels (angiogenesis) in the heart, and improve blood flow and oxygen delivery to the heart muscle.

“We will be tracking patients to see how they’re doing,” said William Suh MD, assistant clinical professor of medicine in the division of cardiology at Geffen School of Medicine.

The goal of this study is to enroll 444 patients nation-wide, of which 222 will receive the stem cell treatment, 111 will receive the placebo, and 111 who will be given standard heart care.